Apparatus and method for coating a material

ABSTRACT

The invention generally provides a method of coating a material, the method including the following steps: (a) forming a generally elongate coating structure ( 15 ), the coating structure having an internal cavity ( 17 ) extending at least substantially along its length, and wherein the internal cavity of the coating structure is capable of receiving a core material ( 21 ); (b) inserting a core material ( 21 ) into the internal cavity ( 17 ) of the coating structure ( 15 ); (c) compressing the coating structure at a first location ( 44 ) along its length so as generally to form a seal at that location; and (d) compressing the coating structure at a second location along its length ( 45 ).

INTRODUCTION

[0001] This invention relates to apparatus and methods for coating amaterial. As will become apparent from the following description, theinvention can be used in many coating applications, however oneapplication to which the invention is particularly suited is in relationto the production of coatings for pharmaceutical capsules, tablets andlike devices for the delivery of pharmacologically active substances(for either human or veterinary use) to a patient. The invention isespecially suited for use in the production pharmaceutical capsules,tablets and like delivery devices where the coating material for thepharmaceutical delivery device is intended to control or delay thetiming of release of a pharmacologically active material containedwithin the “core” of the device. While noting the invention'ssuitability in a broad range of applications, it will be described inthe following description with particular reference to thepharmaceutical coating application to which it is particularly suited.

BACKGROUND TO THE INVENTION

[0002] In order for an effective dosage regimen to be delivered, manypharmaceutical substances must be administered according to exacting oroccasionally, complex dosage regimes. Compliance with such regimes isparticularly important in, for example, many third world countries,where patient compliance with a dosage regimen may be impaired due tothe patient's inability to understand the nature of the dosage regimenrequired, or the need for compliance. Similarly, the treatment ofinfants by a repeated course of injections can be particularly traumaticto the infant patients concerned, and the delivery of the regimen by areduced number of doses whose release profile is controlled, isparticularly desirable. Another important scenario where controlledrelease delivery can be particularly advantageous (compared to repeatedapplication of individual doses) is in veterinary medicine. Many animalsreact extremely adversely to the infliction of pain by (for example)repeated injections. In the veterinary treatment of animals, it can beparticularly difficult to ensure that the animal has received the dosagerequired of the pharmaceutical agent concerned (particularly, forexample, if the pharmaceutical agent involved must be administered inminute quantities, such as, for instance, with reproductive hormonesused in animal husbandry). Repeated handling of an animal to administerdrugs to it not only runs the risk that the animal will refuse toco-operate with the handler, and that the required dose of the drug maynot in fact be delivered, but also, it runs the increased risk of injuryto the animal handler that must administer the drugs.

[0003] The use of controlled release pharmaceutical delivery devices istherefore particularly desirable in many instances, including thosedescribed above. However, the delivery of drugs via controlled releaseregimens is not as widespread as might be hoped, because the productionof suitable delivery devices for the controlled release ofpharmacologically active substances is presently limited by themanufacturing methods and production apparatus that have been used todate to make them.

[0004] Several methods have been employed to date in order tomanufacture controlled release delivery devices to contain a dose of apharmaceutical agent in the form of (for example) a tablet. One methodthat has been employed is injection moulding. This technique involvesthe injection of a heated coating material (typically, apharmaceutically acceptable polymer) under pressure into a mould for adelivery device (in the form of, for example, part of a container). Oncethe coating material has cooled and solidified to a suitable extent, themould is opened for ejection. The part container must then be filledwith the pharmaceutical agent it is intended to contain, and it mustthen be sealed. This technique has significant limitations, particularlyfor the mass production of controlled release pharmaceutical deliverydevices. For one thing, as explained above, it results in the productionof only a partial container. This means that the process of producing acontrolled release drug delivery device via the injection mouldingmethod is a multi-step procedure, which requires sequentially (i) first,the production of a partial container, (ii) filling the partialcontainer with the required dose of the drug it is intended to contain,and (iii) then sealing the container. This sequential, multi-stepprocedure is inefficient as a manufacturing process. It also involves atime delay between the initial step of manufacturing thepartial-container and the subsequent steps of filling it with thepharmaceutical moiety and sealing the container, which can give rise todifficulties as regards ensuring that the finished product issufficiently sterile for use in human or veterinary medicine.

[0005] A second technique is available for manufacturing pharmaceuticaldelivery devices in such a way as to overcome the sterility problemsdescribed earlier that affect the injection moulding procedure. In thepharmaceutical context, to date, the second technique appears to havebeen used solely in the manufacture of sterile vessels to containliquids like physiological saline or water for injection. This secondtechnique is referred to in the art as the “blow-fill-seal” (or the“form-fill-seal”) method. In this technique, a polymer (usually aplastics material) is melt-processed and extruded from a die to form alength of tube. When extruded, the tube is sufficiently hot to bemalleable, but not so hot as to be liquid, and therefore, so as to beuncontrollable in the subsequent steps involved in the manufacturingprocess. A multi-piece die (containing a mould which encompasses thelength of extrudate) then clamps around the length of extrudate (whichis known as the “parison”), thereby sealing one end of the parison, andleaving the other end gripped by the die, but slightly open. The parison(which at this stage of the process, remains hot and malleable) is athin tube which is suspended within the mould cavity. Air is theninjected into the interior of the parison so as to inflate it, so thatit assumes the shape of the mould. The inflated parison is then filledwith the desired contents by an injection process, and is then sealed.The die is then opened to release the finished product. The“blow-fill-seal” technique is similar in many respects to injectionmoulding. It is therefore subject to at least some of the same problemsthat apply to the injection moulding technique.

[0006] The present invention aims to avoid one or more difficultiesassociated with the prior art manufacturing techniques described above,and the apparatus used to perform them.

GENERAL DISCLOSURE OF THE INVENTION

[0007] The invention generally provides a method of coating a material,the method including the following steps:

[0008] (a) forming a generally elongate coating structure, the coatingstructure having an internal cavity extending at least substantiallyalong its length, and wherein the internal cavity of the coatingstructure is capable of receiving a core material;

[0009] (b) inserting a core material into the internal cavity of thecoating structure;

[0010] (c) compressing the coating structure at a first location alongits length so as generally to form a seal at that location; and

[0011] (d) compressing the coating structure at a second location alongits length.

[0012] The method may be performed sequentially in the order of steps(a) to (d) set out above, or the steps of the method may be performed inanother sequence. A preferred sequence is (from first to last step):

[0013] Step (a) (first step)

[0014] Step (c) (second step)

[0015] Step (b) (third step)

[0016] Step (d) (fourth step).

[0017] Preferably, the step of forming the coating structure involvesextruding it from an extrusion means. In this embodiment of theinvention, the coating structure must be an extrudable material, such asa plastics material which is amenable to processing techniques such asmelt-processing and extrusion when heated. The extrusion means could forexample, take the form of a die which extrudes the coating structure inlengths of any desired cross-sectional shape. Preferably, thecross-sectional shape of the coating structure formed by the extrusionmeans is circular, so that in its three-dimensional configuration, thecoating structure generally has the appearance of a tubular structure.The coating structure's cross-sectional shape could take any desiredform however, including generally square, triangular, elliptical, ovoidor more complex shapes. The proviso here is that the cross-sectionalshape must be a closed shape (such as the shapes described earlier), sothat the extruded coating structure can be sealed when it is subjectedto the compression steps of the method, described earlier. Thecross-sectional shape adopted for the coating structure in any contextmay depend on the application to which the coated material produced bythe coating method is to be put.

[0018] In one form of the invention, the coating structure comprises asingle layer of the material from which it is formed. In other forms ofthe invention however, the coating structure may contain two or morelayers of the same or of different materials from which it is formed.Forming the coating structure from two or more layers may be preferredwhere it is desired to control in a particular manner, the releaseprofile of the core material from a finished container produced by themethod. By forming the layers of the coating structure from materialshaving different degradation or permeability characteristics, adifferential rate, onset or profile of release of the core material intoa surrounding environment, as desired, could therefore be established.

[0019] Preferably further, in step (d) of the method, a seal is formedat the location of the second compression along the length of thecoating structure, so as to define a closed container which comprisesthe coating structure sealed at two opposed ends, and containing thecore material in its internal cavity. Preferably, the seal at each endof the container is formed by compressing two mutually opposed surfacesof the coating material so that they come into contact with one anotherin a sealing manner. A seal at any location could also be formed inother ways however, such as by heating the coating structure in additionto compressing it at the location concerned. The step of compressing thecoating structure at any location could also involve cutting the coatingstructure at each of the first and second locations along its length, soas to define a free-standing container separated from the remainingcoating structure from which the container was formed. Preferablyfurther, such a container would have the appearance of a capsule, suchas that of a conventional pharmaceutical capsule.

[0020] In some applications, it might be desirable to produce acontainer which is sealed at one end, but not at the other. In such acase, in step (d) of the method, the step of compressing the secondlocation along the length of the coating structure could take the formof simply cutting it by using a cutting means, rather than forming aseal at that end. This version of the method might be used so as, forexample, to form a pharmaceutical delivery device having one sealed endand one “open” end, so as to provide a delivery device which in use,would encourage the egress of the core material into a patient, from the“open” end of the device.

[0021] In other applications, it may be preferred to form a containerwhich is completely unsealed at one end, and is “generally” sealed atthe other. By “generally” sealing the container at the other end(meaning the first location along the length of the coating structure,in the description set out herein), and further, by reference in step(c) of the first aspect of the invention, mentioned earlier, to“generally forming a seal”, it is to be understood that a closure whichfalls somewhat short of a full or complete seal, is also comprehended.Thus, the formation of a partial seal at that location would be embracedby this feature of the invention.

[0022] Preferably further, the method would be suitable for continuousoperation, or for repeated operation, along the length of the coatingstructure. In this way, the method could be used to generate a desirednumber of individual containers each containing a length of the coatingstructure which are sealed as desired, and each of which contains anamount of the core material in its internal cavity. It is even furtherpreferred that automation means be provided to operate the method, sothat a convenient integrated method is provided for producing a desirednumber of containers as described above.

[0023] In a particularly preferred embodiment of the invention, themethod is used to produce pharmaceutical delivery devices, such ascoated capsules, coated tablets and the like. In this embodiment of theinvention, the coating structure takes the form of a pharmaceuticallyacceptable substance or combination of such substances. Typically, thecoating will comprise a pharmaceutically acceptable polymer orco-polymer, such as a plastics material. Particularly preferredsubstances for the coating material include polylactide-co-glycolidepolymers, polyesters, polysaccharides, polyamides, poly (amino acids),poly (ortho esters), polyanhydrides, polyphosphoesters and polymersformed through combinations of chemical bonds (such as pseudo-peptides,poly (phosphoester-urethanes) and polydepsipeptides). The core material,in this embodiment of the invention contains the pharmacologicallyactive substance (for convenience called the “bioactive” in theremainder of this specification) whose release profile is desired to becontrolled by the provision of the coating structure. The bioactive canbe any suitable pharmacologically active substance. Typically, thebioactive would be a hormone or a vaccine, although the method isapplicable to producing pharmaceutical delivery devices suitable for abroad range of bioactives, including natural, synthetic or recombinantpharmacological agents, food additives or food supplements, antigens,antibodies, cytokines, growth promotants, hormones, cancer cellinhibitory agents, immuno-suppressants or immuno-stimulants,anti-microbial agents (including antibiotics), anti-viral agents,vitamins, vaccines, minerals, and organic or inorganic nutrients. Abioactive core material for use in the invention may consist of one typeof the aforementioned substances, or may include combinations of two ormore such substances.

[0024] The bioactive (or a composite core material in which it iscontained) could also take any number of physical forms, such as in theform of a tablet, a gel, a paste, as granules, in powder form, or afluid, as well as others. The core material could also containadditional materials to the bioactive itself, including pharmaceuticallyacceptable carriers and excipients (including dispersion media,coatings, antibacterial, anti-fungal and/or anti-viral agents and thelike, as well as salts such as di-calcium phosphate), inert (andpharmaceutically acceptable) materials designed to control further therelease of the bioactive in a desired manner, and other like materials,as desired. For example, the core material could also contain ahydrophilic material to encourage the entry of water into the device(such as for example, a swelling agent, such as a “hydrogel”) or asubstance affecting the osmotic interaction of the core material with anexternal biological fluid. Additional components could include:

[0025] (i) binders, such as gum tragacanth, acacia, corn starch orgelatine;

[0026] (ii) disintegrating agents, such as corn starch, potato starch,alginic acid and the like;

[0027] (iii) lubricants, such as magnesium stearate;

[0028] (iv) explosive combinations (eg, citric acid/sodium carbonate);

[0029] (v) surfactant materials or other surface active molecules (eg,proteins, such as albumins, biological detergents and tweens);

[0030] (vi) solubility enhancers (eg, sodium citrate, sodiumbicarbonate, magnesium carbonate);

[0031] (vii) absorbance enhancing agents;

[0032] (viii) lubricants;

[0033] (ix) flow promoters;

[0034] (x) plasticisers;

[0035] (xi) antisticking agents: and/or

[0036] (xii) anti-static agents.

[0037] As would be apparent to those skilled in the art, inpharmaceutical applications of the invention, all such additionalcomponents must be at least substantially pharmaceutically pure,non-toxic in the amounts used, and biocompatible with the bioactive(s)used and with the coating material.

[0038] The invention also provides an apparatus for coating a material,the apparatus including:

[0039] (a) means for forming a generally elongate coating structurehaving an internal cavity extending at least substantially along itslength, and wherein the internal cavity of the coating structure iscapable of receiving a core material;

[0040] (b) means for inserting a core material into the internal cavityof the coating structure;

[0041] (c) means for compressing the coating structure at a firstlocation along its length so as generally to form a seal at thatlocation; and

[0042] (d) means for compressing the coating structure at a secondlocation along its length.

[0043] Preferably, the means for forming the elongate structure areextrusion means, as discussed earlier.

[0044] As explained above, the core material could take any number ofphysical forms, such as in the form of a tablet, a gel, a paste, asgranules, in powder form, or as a fluid, as well as others. The meansfor inserting the core material into the coating structure couldtherefore take any number of forms, according to the nature of the corematerial to be inserted into the coating structure For example, wherethe core material takes the form of a gel or paste, the means forinserting it into the coating structure could take the form of a nozzledesigned to inject the core material into the internal cavity of thecoating structure.

[0045] The means for compressing the coating structure at the firstlocation could, for example, take the form of a mechanism for simplypressing two opposed surfaces of the coating structure together. Suchmeans could also include means for forming a cut through the coatingstructure at that location. The means for compressing the coatingstructure at the second location could also take a similar form, howeverthey could, if desired, take the form of a mechanism for forming anon-sealing open cut at the second location, so as to form a capsulewith an open end at the second location.

[0046] Preferably, the apparatus is suitable for continuous, or repeatedoperation along the length of the coating structure, so as to lenditself to mass production of segments of a coated material, in the formof capsules or like devices.

[0047] The invention further provides a coated material produced by aprocess which includes the steps of:

[0048] (a) forming a generally elongate coating structure, the coatingstructure having an internal cavity extending at least substantiallyalong its length, and wherein the internal cavity of the coatingstructure is capable of receiving a core material;

[0049] (b) inserting a core material into the internal cavity of thecoating structure;

[0050] (c) compressing the coating structure at a first location alongits length so as generally to form a seal at that location; and

[0051] (d) compressing the coating structure at a second location alongits length.

[0052] Preferably, the coated material produced by the process takes theform of a coated tablet, coated capsule or a like device. Preferablyfurther the coated structure is suitable for use as a controlled releasedevice for delivering an amount of the core material in a predeterminedmanner. It is particularly preferred that in such a device, the corematerial contains a pharmacologically active substance, such as any ofthe bioactives described earlier. The process could also be configuredto produce a coated material containing multiple units of the samebioactive, or a two or more units of different bioactives.

BRIEF DESCRIPTION OF THE DRAWINGS

[0053] The invention will now be described by way of example only withreference to the following drawings, in which:

[0054]FIG. 1a represents a side cross-sectional view of an apparatusconstructed in accordance with the invention, for use in coating amaterial;

[0055]FIG. 1b represents a cross section of the apparatus depicted inFIG. 1a, taken along the line A-A. and when viewed in the direction ofthe arrow B;

[0056]FIG. 2 represents a side cross-sectional view of a secondapparatus for coating a material, constructed in accordance with theinvention;

[0057]FIG. 3 depicts a modified version of the embodiment of theinvention shown in FIG. 2;

[0058]FIG. 4 represents a rear loading forming apparatus constructed inaccordance with a fourth embodiment of the invention (being an enlargedview of part of the apparatus depicted in FIGS. 7-9);

[0059] FIGS. 5(a) to (c) depict three different embodiments of a formingapparatus for use in the invention;

[0060] FIGS. 6(a) to (c) depict three further embodiments of a formingapparatus for use in the invention;

[0061] FIGS. 7-9 depict sequential stages of a capsule-coating processand system utilising a fourth embodiment of the invention;

[0062]FIG. 10 is an enlarged schematic view of a coated capsule made inaccordance with the invention; and

[0063]FIG. 11 is a graph which charts the results of an experimentperformed in rats to measure the controlled release (delay) of abioactive formulation made in accordance with the invention, relative toa control group.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION

[0064] Referring now to the drawings, FIG. 1a shows an apparatus(generally denoted 1) for coating a material, constructed in accordancewith a first embodiment of the invention. Apparatus 1, which is shown incross section from the side, is an apparatus which could be used forcoating capsules, such as pharmaceutical capsules. As can be seen fromFIG. 1a, apparatus 1 consists of an extruder barrel (generally denoted3), having an internal bore 5, and a threaded extruder screw 7 locatedand supported for rotation inside the bore 5, by any suitable means,such as those that would readily understood by persons skilled in theart.

[0065] The extruder barrel 3 includes a cross head die 9 near its distalextremity. In use of apparatus 1, a flowable coating material is placedin bore 5, and by rotating extruder screw 7 about its longitudinal axisD within bore 5 in a direction so as to convey the flowable coatingmaterial towards the cross head die 9, is extruded from an opening 11 onthe cross head die. The cross head die 9 includes an extrusion sleeve13, whose longitudinal axis F is at right angles to the longitudinalaxis D of the extruder screw 7. As shown more particularly in FIG. 1b,extrusion sleeve 13 is of generally circular shape when viewed incross-section, in the embodiment of the apparatus shown. When theextruder screw 7 is rotated within bore 5, this motion causes agitationof the flowable coating material so that it is moved towards and ontothe outer surface 12 of extrusion sleeve 13, from within bore 5.Ultimately, such agitation causes the flowable material to exit from theopening 11 (which, by virtue of the cross sectional shape of extrusionsleeve 13, means that in the embodiment shown in FIGS. 1a and 1 b,opening 11 is a generally annular opening). This in turn results in anelongate, generally tubular coating structure 15, formed from theflowable material, being extruded from the apparatus, as shown in FIG.1a. This generally tubular coating structure can be used to coat amaterial within its internal cavity 17, which generally takes the formof a lumen.

[0066] As shown more particularly in FIG. 1a, extrusion sleeve 13 has aninternal bore 19. This internal bore is designed to receive a material21 (which in FIG. 1 is shown as being in the form of a generallycylindrical tablet or pellet) within it, so that material 21 may beconveyed to the end 23 of the extrusion sleeve, where it is enters thecavity 17 and is encapsulated by the generally tubular coating structure15. In the embodiment of the apparatus 1 shown in FIGS. 1a and 1 b, theextrusion sleeve is configured so that the material 21 to undergocoating is fed into the internal bore 19 from an upwardly disposed end25 of the extrusion sleeve, so that it falls within the extrusionsleeve's internal bore under the influence of gravity, so as to beconveyed to and to exit from the lower end of the extrusion sleeve, forcoating by the generally tubular coating structure. In other embodimentsof the invention, the extrusion sleeve might not be so disposed withinthe apparatus, and means other than gravity could be used to convey thematerial 21 to the coating point. Those skilled in the art would readilyunderstand that such means could take any number of forms. In theembodiment of the invention shown in FIGS. 1a and 1 b, the material 21to undergo coating is fed into the generally tubular coating structure15 in the same direction as the egress of that structure from theapparatus 1. In this specification, an arrangement whereby the directionof feed of the coating material is the same as the direction of egressof the coating structure from the general forming apparatus is termed“rear loading”.

[0067] A different embodiment of an apparatus for coating a material anda coating method in accordance with the invention is shown in FIG. 2. Inthe description that follows, for ease of reference and comparison,features depicted in the embodiments described hereafter that correspondto similar features depicted in FIGS. 1a and 1 b will be accorded thesame reference numerals. In FIG. 2, the apparatus (also generallydenoted 1) also includes an extruder barrel 3, having an internal bore 5and an extruder screw 7, as in the first embodiment of the inventiondiscussed earlier. However, in this embodiment, the end of the extruderbarrel takes the form of a tube die 27, rather than a cross head die. Inthis embodiment, the flowable coating material is extruded from anopening 11 located at the end of the apparatus 1, so that it is extrudedin the direction of the arrow G shown in FIG. 2, that is, in a directiongenerally parallel to the longitudinal axis H of the apparatus 1. Theopening 11 from which the flowable coating material is extruded is alsocircular in shape, when viewed in the direction of the arrow J shown inFIG. 2. Opening 11 is an annular hole defined by a circular aperture inthe end wall 29 of the apparatus 1, and by a circular forming means 31located within that circular aperture. The circular aperture 29 and theforming means co-operate so that the flowable coating material isextruded as a generally tubular coating structure from the opening 11. Amaterial 21 to be coated is positioned ahead of the direction of flow ofthe coating structure 15 so as to be fed into, or is fed into theinternal cavity 17 of that structure by movement in a direction oppositeto the direction of egress of the coating structure 15 from apparatus 1.In this specification, such an arrangement for coating a material withthe coating structure formed within apparatus 1 is termed “frontloading”.

[0068] A further, slightly modified version of a front loading coatingapparatus constructed in accordance with the invention, is shown in FIG.3. The apparatus is substantially the same as that depicted in FIG. 3,except that it also includes the use of an additional forming means 33,which in the embodiment shown, takes the form of a generally tubularstructure which is adapted to enter the cavity 17 of the generallytubular coating structure 15. A material 21 to be coated is introducedinto the lumen 35 of the tubular forming means 33, and conveyed by anysuitable means (such as, for example, by an injection of air into thelumen at the opposite end of the forming means 33) to place the material21 within the coating structure, so as to coat the material. The formingmeans 33 would desirably be readily retractable from the tubular coatingstructure 15.

[0069] The embodiments of the method described above each involve theinitial step of forming a generally elongate coating structure (in theform of the generally tubular coating structure 15), via a formingmeans. Generally, an extrusion process would be best suited for thispurpose, although other methods of forming the coating structure may beused in the invention. Where an extrusion process is used, the materialused to form the coating structure must be amenable to manipulation byprocesses such as melt-processing, so that the material can be suitablyextruded from the forming apparatus to give rise to the coatingstructure in the desired conformation. For pharmaceutical applications,suitable materials would generally include pharmaceutically acceptablepolymers, such as pharmaceutically acceptable plastics. Examples ofpharmaceutically acceptable polymers would includepolylactide-co-glycolide polymers, polyesters, polysaccharides,polyamides and poly (amino acids), poly (ortho esters), polyanhydrides,polyphosphoesters and polymers formed through combinations of chemicalbonds (such as pseudo-peptides, poly (phosphoester-urethanes) andpolydepsipeptides). Other suitable materials could be used, the natureof which would be apparent to those skilled in the art.

[0070] In each of the embodiments described earlier, the method involvesthe second step of inserting the core material into the internal cavityof the coating structure. The nature of the core material will vary inaccordance with the nature of the application to which the invention isto be put. In pharmaceutical applications, the core material willgenerally contain a bioactive. A broad range of hormones, including bothsteroid and non-steroidal hormones, and many types of vaccines, wouldconstitute suitable bioactives for this purpose.

[0071] In pharmaceutical applications of the invention, the bioactivewould often be included as part of a composite core material, whichcould take any number of physical forms. For example, the bioactivecould be contained in the form of a tablet, a gel, a paste, as granules,in powder form, as well as combinations of the foregoing, and otherphysical forms. In pharmaceutical applications, the core material wouldoften contain additional substances to the bioactive itself, includingpharmaceutical excipients, inert and pharmaceutically acceptable)materials which might be designed to control the release of thebioactive in a particular manner, and other like materials, as desired.Examples of additional materials which could be contained within thecore material include hydrophilic materials to encourage the entry ofwater into a coated pharmaceutical delivery device (such as for example,swelling agents, such as a “hydrogel”) could be used for this purpose,as could substances affecting the osmotic interaction of the corematerial with an external fluid (such as a biological fluid). Additionalcomponents include:

[0072] (i) binders, such as gum tragacanth, acacia, corn starch orgelatine;

[0073] (ii) disintegrating agents, such as corn starch, potato starch,alginic acid and the like;

[0074] (iii) lubricants, such as magnesium stearate;

[0075] (iv) explosive combinations (eg, citric acid/sodium carbonate);

[0076] (v) surfactant materials or other surface active molecules (eg,proteins, such as albumins, biological detergents and tweens);

[0077] (vi) solubility enhancers (eg, sodium citrate, sodiumbicarbonate, magnesium carbonate);

[0078] (vii) absorbance enhancing agents;

[0079] (viii) lubricants;

[0080] (ix) flow promoters;

[0081] (x) plasticisers;

[0082] (xi) antisticking agents; and/or

[0083] (xii) anti-static agents.

[0084] As explained earlier, and as would be apparent to those skilledin the art, in pharmaceutical applications of the invention, all suchadditional components must be at least substantially pharmaceuticallypure, non-toxic in the amounts used, and biocompatible with thebioactive(s) used and with the coating material.

[0085] The means employed for inserting the core material into theinternal cavity of the coating structure will also depend upon thenature of the core material adopted in any particular application.Generally, the means for inserting the core material into the coatingstructure will include a chute or nozzle into which the core material isintroduced, and by which it is inserted into the coating structure. Suchmeans could also include apparatus for pushing the core material into adesired position within the coating structure (eg, an injection of airto convey the core material to, or to position the core material inplace in the coating structure). If the core material is a tablet, itcould be deposited into position with, for example, a pushrod whichretracts clear of the coating structure prior to its compression by acompression means. Where the core material in the form of a liquid,paste, granules or in a powder form, the means for inserting it into thecoating structure may take the form of an injection apparatus to injectit into the coating structure as appropriate. The injection mechanismused would be designed so as to be retractable from the coatingstructure prior to any compression step occurring.

[0086] Where the coating structure has been formed by melt-processingand extrusion, it may be necessary to cool the extrudate so that itsolidifies to a suitable extent to enable the core material to be loadedinto it, and at the same time, not damaged. Any suitable means (such asthose that would be apparent to persons of ordinary skill in the art)could be used for this purpose. It is particularly desirable that thecooling processes cool the extrudate at such a rate so that when thetime comes for the core material to be inserted into it, it has cooledto a sufficient extent to be able to receive the core material safely.

[0087] The third step of the production method involves the step ofcompressing the coating structure at a first location along its lengthso as generally to form a seal at that location. The purpose ofcompressing the coating structure is to compress, seal and (whereappropriate), to cut the coating structure at the point wherecompression occurs. Examples of apparatus that could be used to performthe first compression step are depicted in FIGS. 5(a) to (c) and FIGS.6(a) to (c). The apparatus depicted in FIGS. 5(a) to (c) take the formof a “scissors” apparatus (generally denoted 35, which includes a pairof blades 37 adapted to slide across one another. The widest section ofthe compressed area along the coating structure should not exceed theoutside diameter of that structure. Thus, the provision of notches (suchas the notches 39 shown in FIGS. 5(a) to (c)) would ensure that the areaof compression on the coating structure is not greater in section thanthe cross-sectional diameter of that structure.

[0088] The means for compressing the coating structure at either thefirst and/or second locations in the process could alternatively takethe form of a “plier” mechanism, where two blades meet one another.FIGS. 6(a) to (c) depict three examples of possible mechanisms forachieving such a compression action. As can be seen, in FIGS. 6(a) to(c). one blade (denoted 40 in each of those drawings) includes a concaverecess 41, whereas its opposed blade includes a mating protrusion 43. Inuse of such plier apparatus in conjunction with the invention, after thestep of inserting the core material into the coating structure hasoccurred in the production method, the filled coating structure would bepassed through the concave part of the plier means, and the two bladeswould be brought together so as to cut through the filled coatingstructure. By virtue of the mating fit of the two blades, the cut formedwould not have a sectional diameter exceeding the cross-sectionaldiameter of the coating structure.

[0089] A third possible compression means would take the form of a plieraction with two blades, where one or both blades have a cutting edgewhich is not sharp. Such a mechanism would simply compress, rather thancut the filled coating structure, and in some applications may benecessary, in combination with a cutting means, to achieve a seal on thefilled coating structure. Whichever form of compression apparatus isused, it could either be free-standing (and capable, if desired, ofbeing manually operated), or more desirably for automated massproduction systems, it would be integrated into, and form part of anintegrated apparatus for carrying out the method aspects of theinvention.

[0090] When the filled coating structure is compressed so as to cut itat two locations along its length, a separated segment of the filledcoating structure is formed. As shown in FIG. 10, in a preferredembodiment of the invention, the segment formed by this method includesa sealed outer layer (consisting of the coating structure (15), which issealed upon itself at each of points 44 and 45, so as to define acapsule which includes a core material 21, within its internal cavity17. The sealing of the capsule formed by this process could also beachieved by means additional to those described above (eg. by heatingthe capsule at each of its ends).

[0091] Desirably, the manufacture of sealed containers (such as the oneschematically depicted in FIG. 10) would be produced by an automated orpartly automated process capable of being performed on a continuous orrepeated basis, so that many such sealed containers could beconveniently produced by operating the process. Such a process isdepicted schematically in FIGS. 7-9. As shown in FIG. 7, a coatingstructure 15 (which when viewed in three dimensions, would have agenerally tubular structure) is extruded from a forming apparatus 1(shown in enlarged view in FIG. 4) onto a conveyor belt 47. Multipleunits of a core material 21 (which might take the form of apharmaceutical tablet) are rear loaded into the internal cavity 17 ofthe extruded core structure 15, via a sleeve 25. As shown in FIG. 8, afirst compression means 49 compresses the coating structure 15 betweeneach of the locations where a unit of the core material 21 has beendeposited. This causes opposed surfaces of the coating structure 15 tobe brought together, by effectively “pinching” them. This first step ofcompression may occur shortly after the coating structure 15 exits theforming apparatus 1, so as to ensure that the core material 21 isproperly retained within the coating structure. This might be importantwhere, for example, the coating structure 15 is extruded downwardly fromthe forming apparatus, so that if compression of the coating structurewere not to occur at that point, the coating material would fall out ofthe coating structure, under the influence of gravity. Such anarrangement is depicted in FIG. 1.

[0092] As shown more particularly in FIG. 9, a subsequent compression isthen performed on the extruded coating structure, at a second location,by a second compression means 51. In the process depicted in FIG. 9, thesecond compression means takes the form of an apparatus which bothcompresses the coating structure, and at the same time cuts it, so as toform individual capsules (each denoted 53), which are conveyed by theconveyor belt to be further processed as desired according to theparticular application to which they are to be put. Such furtherprocessing might, for example, take the form of heating the ends of thecapsules so as to seal them more effectively, if so required for anyparticular application.

[0093] Many variations of the process described above can of course bemade, without departing from the general concept of the invention. Forexample, an automated processing system embodying the inventive conceptcould include more than two compression/cutting mechanisms, to achieveproduction efficiencies. Further, the profile of the filled coatingstructure could be collapsed between individual units of the corematerial contained within it, by restricting the ingress of air. Thiscould be achieved, for example, by limiting the ingress of air into thecavity of the coating structure at predetermined times in theperformance of the process (typically, between the insertion of units ofthe core material). This might aid the process of sealing individualcoated structures. The cutting and sealing of loaded sections from alength of extrudate could be achieved with a blade (either cold orheated), a saw, a pinching mechanism, or a non-mechanical cutter, suchas a laser. The appropriate cutting and sealing mechanism(s) would bechosen to suit the particular application.

[0094] Co-ordination of the various process steps involved in producingcoated structures such as those described above could be achieved by anysuitable means, including mechanical means (eg where the movement of allmoving parts is mechanically synchronised), or by electromechanicalmeans (where the motion of moving parts is controlled electronicallyfrom sensors appropriately positioned to detect the status of thevarious stages of the process). Hydraulic or pneumatic components usedin the apparatus and process could conveniently be controlled in thismanner. In many modern manufacturing plants, the process wouldadditionally be controlled by computerised means.

[0095] The sealed structures produced by the method and apparatusaspects of the invention could take many forms, and could be produced ina broad variety of sizes and dimensions (including conceptually, evenmicro and even nano-particulate sizes). Such containers could be put toa broad variety of uses, and it is to be understood that invention is byno means limited to the pharmaceutical applications which have beendiscussed earlier in this specification. For example, sealed containersmade in accordance with the apparatus and method aspects of theinvention could be used to encapsulate transponders for injection intoanimals, for veterinary identification. Further, such coated structurescould also be used for producing controlled release devices forreleasing agricultural chemicals into the environment (eg, forfertilising the growth of plants). It is therefore to be understood thatthe invention is capable of many modifications and/or variations, andthat the spirit and scope of the invention is by no means limited to thedetails of the preferred embodiments described earlier. It is thereforeto be understood that the spirit and scope of the invention extends toevery novel feature and combination of features disclosed herein.

EXAMPLES

[0096] The following non-limiting examples of the invention are givenbelow.

[0097] A. In Vitro Experiments

[0098] In a first set of experiments, the applicants prepared controlledrelease containers in accordance with the method aspect of theinvention, and measured the latency of release from those containers, ofa bioactive release “marker” (Methylene Blue) in an in vitro settingapproximating typical physiological conditions in a mammalian species.The details of the experiments conducted and the results obtained fromthem are set out below.

[0099] In the experiments, four (4) batches of “Resomer” coated tablets,approximately 25 mm in length and of 3 mm external diameter wereproduced for testing, as follows. (It should be noted that the term“Resomer” is a trade mark of the Boehringer Ingelheim corporate group).

[0100] Materials Used

[0101] Polymers

[0102] Polymer formulations used were:

[0103] 1 R206 (as supplied by manufacturer);

[0104] 2 RG858 (as supplied by manufacturer);

[0105] 3 RG506 (as supplied by manufacturer); and

[0106] 4 RG504 (as supplied by manufacturer).

[0107] (The “manufacturer” was the Boehringer Ingelheim corporategroup).

[0108] Resomer poly-d,l-lactide, R206 (i.v.=1.0; 200 g: Batch #241888)was obtained from Boehringer Ingelheim.

[0109] Resomer 85:15 poly-d,l-lactide-co-glycolide copolymer, RG858(i.v.=1.4; 200 g: Batch #261073) was obtained from Boehringer Ingelheim.

[0110] Resomer 50:50 poly-d,l-lactide-co-glycolide copolymer, RG506(i.v.=0.8; 200 g: Batch #34034) was obtained from Boehringer Ingelheim.

[0111] Resomer 50:50 poly-d,l-lactide-co-glycolide copolymer, RG504(i.v.=0.4; 200 g: Batch #34015) was obtained from Boehringer Ingelheim.

[0112] Chloroform (HPLC grade) was from BDH (Hypersolv).

[0113] All other chemicals and reagents were generally analyticalreagent grade.

[0114] Gel Permeation Chromatography (GPC)

[0115] Gel Permeation High Performance liquid chromatographic analysiswas used to confirm the repeatability of production of controlledrelease devices using the apparatus and method aspects of the invention.

[0116] The GPC-HPLC system consisted of a Hewlett Packard 1050 seriespump and auto-sampler. This was connected with a series ofHewlett-Packard and PLgel columns (polystyrene-divinylbenzene),consisting of one PLgel 10 μm mixed-B (#10 μMIXB8434) and two HP/PLgel 5μm mixed-D columns (#'s 5μ48879 and 5 μ523413), 300×7.5 mm each, and aPLgel guard column (5 μm; 5×100 mm). A Sedex 55 Evaporative LightScattering detector operating at a temperature of 35 degrees Celsiuswith nitrogen gas purge/nebuliser was used for peak detection. Thesystem was run isocratically with chloroform as the mobile phase at aflow rate of 1.0 ml/min.

[0117] Samples of polymer extrudate were prepared for molecular weightanalysis using Gel Permeation Chromatography (GPC) by dissolving thesample (about 20 mg) in chloroform (1.0 ml). Samples (400 μl) were thenplaced in auto-sampler vials containing a Flow Rate Marker (“FRM”; 25μl), sealed and then run through the HPLC system. The sample injectionvolume was 10 μl.

[0118] Molecular weights (M_(n) and M_(w)) were calculated from dataacquired by Hewlett Packard Chem Station Software and treated usingproprietary GPC analysis software after setting integration limitsmanually. Calibration used a series of polystyrene standards (M_(r):2880000, 1290000, 560000, 66000 and 10100 atomic mass units (“amu”)).The polydispersities of the standards were 1.03-1.06 for all standards.Standard samples were run subsequent to every sixth or seventh sample.

[0119] GPC Data Analysis

[0120] GPC data analysis entailed the following procedure:

[0121] raw data files in HPChem Station format were downloaded forimportation into the proprietary GPC analysis software;

[0122] the standards from each run were analysed to ensure no anomalousoccurrences had arisen during the chromatographic run. The latter wasdetermined as follows.

[0123] comparison of the Peak Volume and Peak molecular weight for eachof the standard samples; followed by

[0124] use of the first standard for column calibration to optimise theanalysis algorithm; with

[0125] the molecular weights of each of the standards, including thefirst standard, then being determined using the calibrated column data.

[0126] The molecular weight of the analysis samples was then calculatedusing the column calibration algorithm established from the appropriategroups of standards.

[0127] Extrusion

[0128] Processing was performed on a Brabender Extruder at the CASEYCentre for Polymer Technology, Dandenong, Victoria, Australia. Theequipment used consisted of the following:

[0129] Brabender Extruder-Plasticorder Type PL2000-6 consisting ofDynamometer (Model No. 814400)

[0130] Interface (Model No. 680118104)

[0131] Temperature Controller (Model No. 680147)

[0132] Single Screw Attachment Type 19/25D

[0133] Haul Off (Model No. 297828)

[0134] Crosshead Die Assembly

[0135] The conditions typically used for extrusion of thed,l-polylactide-co-glycolide polymers are given in Table 1 below. Theprocedure for setup and extrusion involved the following:

[0136] 1 When the temperatures had stabilised in the apparatus, theextruder barrel was purged with Ethylene vinyl acetate (EVA). When thepurge material appeared clear of any contaminant the barrel was left torun empty.

[0137] 2 The screw and haul-off belt speeds were then set appropriatelyfor the material.

[0138] 3 Polymer was loaded into the feed throat and pushed, stuffed orstarve fed as required.

[0139] 4 Air cooling of the extrudate was set up as required.

[0140] 5 The first material through was assumed to be contaminated withpurge polymer and was discarded (approximately the first 50 grams).

[0141] 6 The resultant polymer extrudate was then hauled off.

[0142] The extruder was then run to empty. TABLE 1 Brabender ExtruderConditions Zone 1 Zone 2 Zone 3 Polymer ID ° C. ° C. ° C. Die ° C. rpmd,l-pLa R206  90 110 125 130 35 d,l-pLa/pGa RG858 110 125 140 165 10(85:15) d,l-pLa/pGa RG506  90 110 125 130 35 (50:50) d,l-pLa/pGa RG504 90 110 125 130 20 (50:50)

[0143] The extrusion conditions for these process runs were dependent onthe individual polymer characteristics. However, the data contained inTable 1 indicate the conditions generally used.

[0144] Each of the four runs progressed relatively smoothly, havingstabilized virtually immediately following commencement of the extrusionprocess. It was observed that samples from the beginning to the end ofthe extrusion run exhibited similar weight average (M_(w)) and numberaverage (M_(n)) molecular weights. The mean molecular weights, relativeto polystyrene, for the selected samples are presented in Table 2. TABLE2 Formulation Details Average Molecular Weight of Unit Samples SelectedSamples Code Formulation Prepared M_(n) M_(w) Polydispersity 1 Resomer160  47300 120833 2.6 R206 2 Resomer 160 156500 260167 1.7 RG858 3Resomer 160  31850  91808 2.9 RG506 4 Resomer 160  5080  17725 3.5 RG504

[0145] In vitro Performance Monitoring

[0146] Samples were placed in approximately 20 ml of phosphate bufferedsaline, (pH 7.2), and held at 37 degrees Celsius. The samples werechecked daily. Checking involved some agitation of thesolution/suspension, albeit not vigorous enough to induce mechanicaldamage. Release of the bioactive marker from any test sample wasdetermined by visual inspection (namely, by the solution turning blue).

[0147] Results

[0148] Polymer Extrusion

[0149] Polymer extrusion with the Brabender extruder proceeded underconditions, and in a manner, consistent with materials of comparablecomposition. Each of the four runs progressed smoothly. GPC-HPLC dataindicated that the extrudate exhibited similar weight average molecularweights throughout the runs. The mean molecular weight of the extrudatewas, in general, equivalent to 90% of the molecular weight of thestarting materials indicating minimal thermal degradation had beeninduced.

[0150] (B) In Vivo Studies

[0151] Outline of Experiments Conducted

[0152] The studies set out in A (above) confirm the suitability ofcontrolled release devices made in accordance with the invention, in anin vitro environment. The applicants also conducted studies to confirmthat the invention could be used to produce devices suitable for use ascontrolled release delivery devices in vivo. These further studies arediscussed below.

[0153] The general nature of the experiment was as follows. Rats wererandomly selected into two groups. The first group (Group B) receivedadministration of an Avidin formulation. The second group (Group A) wasadministered the same Avidin formulation, however, presented in the formof a controlled release delivery device made in accordance with theinvention. The time delay to the appearance of antibodies in each groupto the Avidin formulation, was measured. The experimental details wereas follows.

[0154] Avidin Formulation

[0155] The Avidin formulation used had the following composition: Avidin5 mg/35 mg Lactose 95.56% (w/w) Magnesium Stearate 3% (w/w) Explotab(Sodium start glycolate) (1.94% w/w)

[0156] Preparation of Implants

[0157] Controlled release delivery devices containing the Avidinformulation were made as follows. Avidin tablets weighing 25 mg werecoated using a plastics extrusion apparatus into which 50:50poly-d,l-lactide-co-glycolide copolymer had been melt processed, so asto form individual coated tablets, of approximately 12 mm length and 3.5mm diameter, in accordance with the method aspect of the invention.

[0158] Animals

[0159] Rats (Sprague-Dawley; Male; 20), mean mass=254 (Stdevp=36 g) wereemployed for the experiment (two randomly selected groups of ten fortesting of response to antigen).

[0160] All animals were given free access to food (Barastoc rodentpellets) and water at all times during the study. All animals wereinspected daily by the animal house supervisor, and thrice weekly fordetailed observation by the applicants' personnel to ensure noadverse/traumatic reactions to the implanting or implants arose.

[0161] Animals were identified using permanent colour marker pens andmarking the animals on the tail.

[0162] Test Groups

[0163] The dose regimens applied to the two experimental groups were asfollows:

[0164] Group A: delayed release “Avidin” (10 animals)

[0165] Group B: “Avidin” only (10 animals)

[0166] Implantation

[0167] Rats were implanted by means of a modified Synovex® implantinggun. Animals were not anaesthetised. The implantation site was shaven,then washed with ethanol (70% v/v) prior to implantation. The implantpuncture wound required no surgical closure.

[0168] Subsequent to implantation, all animals were observed for traumaand/or abnormal behaviour for 180 minutes. No abnormal behaviour wasobserved during this period. Minimal wound bleeding was observed duringthe observation period. Examination of the animals 24 hours afterimplantation showed all wounds had sealed with no signs of infection.

[0169] ELISA Testing Protocol

[0170] Nunc “Immuno” Microtiter plates were coated with 30 μl of antigen(Avidin stock solution; 10 mg/ml) at 5-50 μg/ml in 0.04 M carbonatecoating buffer. The plates were incubated at 37° C. for 1 hour.

[0171] Control test groups of the following composition were run withthe test serum:

[0172] No antigen, Antibody, Horse Radish Peroxidase (HRP), TMB

[0173] No antigen, No antibody, No HRP, TMB

[0174] Antigen, No antibody, HRP/TMB

[0175] Antigen, known positive antibody, HRP/TMB

[0176] Coated plates were washed with water (3×) or saline/Tween 20.

[0177] Unbound sites were blocked by incubating for 60 minutes at 37° C.using 300 μl/well of 1% BSA in PBS plus 0.1% Tween 20 in PBS.

[0178] “Blocked” plates were washed (3×) with saline/Tween 20.

[0179] Test serum samples (50 μl) diluted 1 in 200 in blocking solutionwere added to test wells and incubated at 37° C. for 90 minutes.

[0180] “Test” plates were washed (3×) with saline/Tween 20.

[0181] Anti-rat conjugated HRP (RAM-HRP; 50 μl/well) diluted 1 in 1000in blocking solution was added and the plates incubated under ambientconditions for 120 minutes.

[0182] Plates were washed (3×) with saline/Tween 20.

[0183] The reaction was initiated by addition of TMB (100 μl/well).Plates were held in a humid box for 60 minutes.

[0184] The reaction was terminated by addition of sulphuric acid (2.0 M;50 μl/well). Plates were held in a humid box for 60 minutes.

[0185] Absorbance readings were taken using a Multiscan plate readerusing Filter 1=4=450 nm and Filter 2=8=690 nm.

[0186] Results TABLE 4 Group 10 Nov 97 17 Nov 97 24 Nov 97 01 Dec 97 08Dec 97 15 Dec 97 17 Dec 97 Mean Group A 0.097 0.094 0.121 0.115 0.2840.428 0.490 Mean Group B 0.095 0.131 0.518 0.612 0.681 0.677 0.622Stdevp Group 0.007 0.010 0.013 0.007 0.307 0.422 0.413 A Stdevp Group0.008 0.038 0.309 0.359 0.391 0.383 0.392 B t-test 0.65 0.02 0.00390.0025 0.028 0.21 0.5 significance values (p)

[0187] The data set out above are represented graphically in FIG. 11 ofthe drawings.

[0188] Conclusions

[0189] These data show a marked delay in the seroconversion of rats inGroup A, relative to those of Group B. When analysed using Student'st-Test, a statistically significant difference between the data for thetwo groups was found at 7, 14, 21 and 28 days following administrationof the formulations to the animals (ie, between Nov. 17, 1997 and Dec.8, 1997). Subsequent to Dec. 8, 1997, the immune response of the animalsin the respective groups showed no statistically significant difference,suggesting that seroconversion in Group A animals had simply beendelayed, and was reaching a similar response level to that observedearlier in Group B. The seroconversion of rats treated with thecontrolled release devices of the invention was therefore delayed-on astatistically significant basis-relative to the delay observed in theGroup B rats.

The claims defining the invention are as follows:
 1. A method ofproducing a delivery device for the controlled release of a bioactivesubstance, comprising the following steps: (a) forming a generallyelongate coating structure to coat a core material containing thebioactive substance, the coating structure having an internal cavityextending at least substantially along its length, and wherein theinternal cavity of the coating structure is capable of receiving a corematerial: (b) inserting the core material into the internal cavity ofthe coating structure; (c) compressing the coating structure at a firstlocation along its length so as generally to form a seal at thatlocation; and (d) compressing the coating structure at a second locationalong its length.
 2. A method as claimed in claim 1, in which thecoating structure is formed by extrusion from an extrusion means.
 3. Amethod as claimed in either of claims 1 or 2, in which the coatingstructure is formed from a pharmaceutically or veterinarily acceptablepolymeric material.
 4. A method as claimed in any of the precedingclaims, in which the coating structure is formed as a single layer.
 5. Amethod as claimed in any one of claim 1 to 3, in which the coatingstructure comprises two or more layers.
 6. A method as claimed in claim5, in which the two or more layers of the coating structure are layersof the same material.
 7. A method as claimed in claim 5, in which thetwo or more layers of the coating structure are layers of two or moredifferent materials.
 8. A method as claimed in claim 3, in which thepharmaceutically or veterinarily acceptable polymeric material isselected from the group consisting of: (a) polylactide co-glycolidepolymers; (b) polyesters; (c) polysaccharides; (d) polyamides; (e) poly(amino acids); (f) poly (ortho esters); (g) polyanhydrides; (h)polyphosphoesters; (i) polymers formed through combinations of chemicalbonds; or combinations of two or more of (a) to (i).
 9. A method asclaimed in claim 8, in which the polymers of group (i) comprise: (i)pseudo-peptides; (ii) poly (phosphoester-urethanes); (iii)polydepsipeptides or combinations of two or more of groups (i) to (ii).10. A method as claimed in any of the preceding claims, in which thecore structure comprises: (a) a tablet; (b) a gel; (c) a paste; (d)granules; (e) powder; (f) a fluid; or combinations of two or more of (a)to (e).
 11. A method as claimed in any of the preceding claims, in whichthe core material comprises: (a) a bioactive substance selected from thegroup consisting of: (i) natural, synthetic or recombinantpharmacological agents; (ii) food additives; (iii) food supplements;(iv) antigens; (v) antibodies; (vi) cytokines; (vii) growth promotants;(viii) hormones; (ix) vaccines; (x) cancer cell inhibitory agents; (xi)immuno-suppressants; (xii) immuno-stimulants; (xiii) antimicrobialagents; (xiv) anti-viral agents; (xv) vitamins; (xvi) minerals; (xvii)organic nutrients; (xviii) inorganic nutrients: or combinations of twoor more of the aforegoing; and (b) optionally, pharmaceutically orveterinarily acceptable carriers and/or excipients.
 12. A method asclaimed in any of the preceding claims, in which the step of compressingthe coating structure at the first location along its length so asgenerally to form a seal at that location comprises the step of bringingtwo or more mutually opposed surfaces of the coating structure intocontact with one another, so as generally to form a seal at thatlocation.
 13. A method as claimed in claim 12, in which the step ofcompressing the coating structure at the first location along its lengthinvolves cutting the coating structure at that location.
 14. A method asclaimed in any of the preceding claims, in which the step of compressingthe coating structure at the second location along its length comprisesthe step of bringing two or more mutually opposed surfaces of thecoating structure together, so as to form a seal at that location.
 15. Amethod as claimed in any of claims 1 to 13, in which the step ofcompressing the coating structure at the second location does not giverise to the formation of a seal at that location.
 16. A method asclaimed in either of claims 14 or 15, in which the step of compressingthe coating structure at the second location comprises cutting thecoating structure at that location.
 17. A method as claimed in claim 14,whereby a generally sealed container is formed.
 18. A method as claimedin either of claims 15 or 16, whereby a container is formed which isgenerally sealed at one of two mutually opposed ends thereof, but not atits other end.
 19. A method as claimed in any of the preceding claims,in which steps (a) to (d) of claim 1 are repeated along the length ofthe coating structure, so as to produce a plurality of coated structuresin the form of controlled release delivery devices for a bioactivesubstance.
 20. A method as claimed in claim 19, in which the methodadditionally comprises automation means to automate the repeatedperformance of the method along the length of the coating structure. 21.A controlled release delivery device for a bioactive substance producedby a method as claimed in any of claims 1 to
 20. 22. A controlledrelease delivery device for a bioactive substance as claimed in claim21, in which the device generally takes the form of a coated capsule ortablet.
 23. An apparatus for producing a controlled release deliverydevice for a bioactive substance, comprising: (a) means for forming agenerally elongate coating structure to coat a core material containinga bioactive substance, and wherein the coating structure has an internalcavity extending at least substantially along its length capable ofreceiving the core material therein; (b) means for inserting the corematerial into the internal cavity of the coating structure; (c) meansfor compressing the coating structure at a first location along itslength; and (d) means for compressing the coating structure at a secondlocation along its length.
 24. An apparatus as claimed in claim 23, inwhich the means (a) are extrusion means.
 25. An apparatus as claimed inclaim 23, in which the means (a) are means for extruding the coatingstructure in the form of two or more layers.
 26. An apparatus as claimedin either of claims 23 or 24, in which the means for compressing thecoating structure at the first location along its length are means whichresult in two or more opposed surfaces of the coating structure beingbrought together, so as thereby generally to form a seal at thatlocation.
 27. An apparatus as claimed in claim 26, in which the meansfor compressing the coating structure at the first location are cuttingmeans.
 28. An apparatus as claimed in any one of claims 23 to 26, inwhich the means for compressing the coating structure at the secondlocation are means which do not form a seal at that location.
 29. Anapparatus as claimed in any one of claims 23 to 26 in which the meansfor compressing the coating structure at the second location are meansfor forming a seal at that location.
 30. An apparatus as claimed in anyone of claims 23 to 29, in which the apparatus is capable of repeatedoperation along the length of the coating structure.
 31. An apparatus asclaimed in claim 30, in which automation means are provided to automatethe production of controlled release delivery devices in accordance withthe method of claim 1.